Abstract 12971: A Novel Combination Therapy with Anti-CD3 Antibody and IL-2 Complexes Against Atherosclerosis Targeting Effector T Cells and Regulatory T Cells
Background: Accumulating evidence suggests that a balance between pathogenic effector T cells (Teffs) and regulatory T cells (Tregs) may be important for the control of atherosclerotic disease. We hypothesized that combination therapy with anti-CD3 antibody (CD3-Ab) and IL-2/anti-IL-2 monoclonal antibody complexes (IL-2 complexes) aimed at increasing the ratio of Tregs to Teffs would effectively inhibit atherosclerosis in mice.
Methods and results: We treated eight-week old apolipoprotein E-deficient mice fed a high fat diet with vehicle (untreated) (n=10), CD3-Ab (50μg/day) (n=11), IL-2 complexes (1 μg recombinant IL-2 plus 5 μg anti-IL-2 mAb per day) (n=12) and their combination (CD3-Ab + IL-2 complexes) (n=11). Flow cytometric analysis of immune cells was performed at 10 weeks of age and atherosclerosis was assessed at 16 weeks old. CD3-Ab monotherapy moderately reduced atherosclerotic lesion formation (aortic sinus mean plaque area: 62.0±2.8х104 to 53.8±2.3х104 μm2, p≤0.05) compared with untreated controls, associated with decreased CD4+ Teffs by 42% (p≤0.05) but no changes in the ratio of Foxp3+ Tregs to Teffs in lymph nodes (LNs). IL-2 complexes significantly inhibited atherosclerosis (50.6±2.9х104 μm2, p≤0.05) by inducing a 2.7-fold increase in Foxp3+ Tregs in LNs compared with untreated controls. Moreover, mice that received a combination therapy had markedly less atherosclerotic lesions (37.2±1.9х104 μm2, p≤0.05) than mice treated with CD3-Ab or IL-2 complexes alone. In combination-treated mice, we observed the highest ratio of Tregs to Teffs in LNs and the largest number of Foxp3+ Tregs within atherosclerotic lesions among the four groups, as well as highly up-regulated expression of activation markers such as CTLA-4 or CD103 in Tregs and increased number of IL-10-producing T cells. Along with this, the combination treatment markedly reduced Ly6Chigh inflammatory monocytes in the blood and macrophages in atherosclerotic lesions, whereas other therapies had less effect.
Conclusions: Our results indicate that in addition to suppressing Teff responses, enhancing Treg-mediated immune responses is more efficacious in preventing atherosclerosis, suggesting an effective therapeutic approach to atherosclerosis.
- © 2013 by American Heart Association, Inc.